Priftin

CLINICAL PHARMACOLOGY

Mechanism Of Action

Rifapentine, a cyclopentyl
rifamycin, is an antimycobacterial agent [see Microbiology].

Pharmacokinetics

When oral doses of PRIFTIN were
administered once daily or once every 72 hours to healthy volunteers for 10
days, single dose AUC (0-∞) of rifapentine was similar to its
steady-state AUCss (0-24h) or AUCss (0-72h) values, suggesting no significant
auto-induction effect on steady-state pharmacokinetics of rifapentine.
Steady-state conditions were achieved by day 10 following daily administration
of PRIFTIN 600 mg. No plasma accumulation of rifapentine and 25desacetyl
rifapentine (active metabolite) is expected after once weekly administration of
PRIFTIN.

The pharmacokinetic parameters
of rifapentine and 25-desacetyl rifapentine on day 10 following oral
administration of 600 mg PRIFTIN every 72 hours to healthy volunteers are
described in Table 5.

The pharmacokinetic parameters
of rifapentine and 25-desacetyl rifapentine following single-dose oral
administration of 900 mg PRIFTIN in combination with 900 mg isoniazid in fed
conditions are described in Table 6.

Absorption

The absolute bioavailability of
PRIFTIN has not been determined. The relative bioavailability (with an oral
solution as a reference) of PRIFTIN after a single 600 mg dose to healthy adult
volunteers was 70%. The maximum concentrations were achieved from 5 hours to 6
hours after administration of the 600 mg PRIFTIN dose.

The administration of PRIFTIN
with a high fat meal increased rifapentine Cmax and AUC by 40% to 50% over that
observed when PRIFTIN was administered under fasting conditions.

The administration of PRIFTIN
(900 mg single dose) and isoniazid (900 mg single dose) with a low fat, high
carbohydrate breakfast, led to a 47% and 51% increase in rifapentine Cmax and
AUC, respectively. In contrast, the ingestion of the same meal decreased
isoniazid Cmax and AUC by 46% and of 23%, respectively.

Distribution

In a population pharmacokinetic
analysis in 351 tuberculosis patients who received 600 mg PRIFTIN in
combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent
volume of distribution was 70.2 ± 9.1 L. In healthy volunteers, rifapentine and
25-desacetyl rifapentine were 97.7% and 93.2% bound to plasma proteins,
respectively. Rifapentine was mainly bound to albumin. Similar extent of
protein binding was observed in healthy volunteers, asymptomaticHIV-infected
subjects and hepatically impaired subjects.

Metabolism/Excretion

Following a single 600 mg oral
dose of radiolabeled rifapentine to healthy volunteers (n=4), 87% of the total 14C
rifapentine was recovered in the urine (17%) and feces (70%). Greater than 80%
of the total 14C rifapentine dose was excreted from the body within
7 days. Rifapentine was hydrolyzed by an esterase enzyme to form a
microbiologically active 25-desacetyl rifapentine. Rifapentine and 25-desacetyl
rifapentine accounted for 99% of the total radioactivity in plasma. Plasma AUC(0-∞)
and Cmax values of the 25-desacetyl rifapentine metabolite were one-half and
one-third those of the rifapentine, respectively. Based upon relative in vitro
activities and AUC(0∞) values, rifapentine and 25-desacetyl rifapentine
potentially contributes 62% and 38% to the clinical activities against M.
tuberculosis, respectively.

Specific Populations

Gender: In a population pharmacokinetics analysis
of sparse blood samples obtained from 351 tuberculosis patients who received
600 mg PRIFTIN in combination with isoniazid, pyrazinamide and ethambutol, the
estimated apparent oral clearance of PRIFTIN for males and females was 2.51 ±
0.14 L/h and 1.69 ± 0.41 L/h, respectively. The clinical significance of the
difference in the estimated apparent oral clearance is not known.

Elderly: Following oral administration of a single
600 mg dose of PRIFTIN to elderly (65 years and older) male healthy volunteers
(n=14), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were
similar to that observed for young (18 to 45 years) healthy male volunteers
(n=20).

Pediatric: In a pharmacokinetic study in pediatric
patients (age 2 to 12 years), a single oral dose of 150 mg PRIFTIN was
administered to those weighing less than 30 kg (n=11) and a single oral dose of
300 mg was administered to those weighing greater than30kg (n=12). The mean
estimates of AUC and Cmax were approximately 30% to 50% lower in these
pediatric patients than those observed in healthy adults administered single
oral doses of 600 mg and 900 mg.

A study compared the pharmacokinetics of rifapentine in
pediatric patients (age 2 years to 11 years) with latent tuberculosis infection
(n=80) receiving PRIFTIN once weekly based on weight (15 mg/kg-30 mg/kg, up to
a maximum of 900 mg, see Table 1) to that of adults (n=77) receiving PRIFTIN
900 mg once weekly. Children who could not swallow whole tablets were
administered crushed tablets mixed in soft food. Overall, the geometric mean
AUC of rifapentine in this age group was 31% higher compared to adult patients
receiving 900 mg PRIFTIN once weekly (720 versus 551 mcg*h/mL). The geometric
mean AUC of rifapentine was 60% higher in children administered whole tablets
(884 versus 551 mcg*h/mL) and 19% higher in children administered crushed
tablets (656 versus 551 mcg*h/mL), as compared to exposures in adults.
Pediatric patients administered crushed PRIFTIN tablets had 26% lower
rifapentine exposures compared to those pediatric patients who were given whole
tablets.

Population pharmacokinetic analysis showed that
rifapentine clearance adjusted to body weight decreased with increasing age of
pediatric patients (2-18 years).

In another pharmacokinetics study of PRIFTIN in healthy
adolescents (age 12 to 15 years), 600 mg PRIFTIN was administered to those
weighing ≥ 45 kg (n=10) and 450 mg was administered to those weighing less
than 45 kg (n=2). The pharmacokinetics of rifapentine were similar to those
observed in healthy adults.

Renal Impaired Patients: The pharmacokinetics of
rifapentine have not been evaluated in renal impaired patients. Although only
about 17% of an administered dose is excreted via the kidneys, the clinical
significance of impaired renal function on the disposition of rifapentine and
its 25desacetyl metabolite is not known.

Hepatic Impaired Patients: Following oral
administration of a single 600 mg dose of PRIFTIN to mild to severe hepatic
impaired patients (n=15), the pharmacokinetics of rifapentine and 25-desacetyl
metabolite were similar in patients with various degrees of hepatic impairment
and to that observed in another study for healthy volunteers (n=12).

Asymptomatic HIV-Infected Volunteers: Following
oral administration of a single 600 mg dose of PRIFTIN to asymptomatic
HIV-infected volunteers (n=15) under fasting conditions, mean Cmax and AUC(0-∞)
of rifapentine were lower (20%-32%) than that observed in other studies in
healthy volunteers (n=55). In a cross-study comparison, mean Cmax and AUC
values of the 25-desacetyl rifapentine, when compared to healthy volunteers
were higher (6%-21%) in one study (n=20), but lower (15%-16%) in a different
study (n=40). The clinical significance of this observation is not known. Food
(850 total calories: 33 g protein, 55 g fat, and 58 g carbohydrate) increases
the mean AUC and Cmax of rifapentine observed under fasting conditions in
asymptomatic HIV-infected volunteers by about 51% and 53%, respectively.

Drug-Drug Interactions

Isoniazid: Co-administration of PRIFTIN (900 mg
single dose) and isoniazid (900 mg single dose), in fasted condition, did not
result in any significant change in the exposure of rifapentine and isoniazid
compared to when administered alone in fasted condition.

Rifapentine is an inducer of cytochrome P4503A4 and
2C8/9. Therefore, it may increase the metabolism and decrease the activity of
other co-administered drugs that are metabolized by these enzymes. Dosage
adjustments of the co-administered drugs may be necessary if they are given
concurrently with PRIFTIN [see DRUG INTERACTIONS].

Indinavir: In a study in which 600 mg PRIFTIN was
administered twice weekly for 14 days followed by PRIFTIN twice weekly plus 800
mg indinavir 3 times a day for an additional 14 days, indinavir Cmax decreased
by 55% while AUC reduced by 70%. Clearance of indinavir increased by 3-fold in
the presence of PRIFTIN while half-life did not change. But when indinavir was
administered for 14 days followed by co-administration with PRIFTIN for an
additional 14 days, indinavir did not affect the pharmacokinetics of
rifapentine [see WARNINGS AND PRECAUTIONS
and DRUG INTERACTIONS].

Fixed dose combination of efavirenz, emtricitabine and
tenofovir: Once-weekly coadministration of 900 mg PRIFTIN with the
antiretroviral fixed dose combination of efavirenz 600 mg, emtricitabine 200 mg
and tenofovir disoproxyl fumarate 300mg in HIV-infected patients did not result
in any substantial change in steady state exposures of efavirenz,
emtricitabine, and tenofovir (Table7). A 15% decrease in efavirenz Cmin and AUC
and a 13% decrease in tenofovir Cmin were observed with repeated weekly doses
of PRIFTIN (Table 7). No clinically significant change in CD4 cell counts or
viral loads were noted.

Microbiology

Mechanism of Action

Rifapentine, a cyclopentyl
rifamycin, inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium
tuberculosis but does not affect mammalian cells at concentrations that are
active against these bacteria. At therapeutic levels, rifapentine inhibits RNA
transcription by preventing the initiation of RNA chain formation. It forms a
stable complex with bacterial DNA-dependent RNA polymerase, leading to
repression of RNA synthesis and cell death. Rifapentine and its 25-desacetyl
metabolite accumulate in human monocyte-derived macrophages and are
bactericidal to both intracellular and extracellular M. tuberculosis bacilli.

Mechanism of Resistance

The mechanism of resistance to
rifapentine appears to be similar to that of rifampin. Bacterial resistance to
rifapentine is caused by an alteration in the target site, the beta subunit of
the DNA-dependent RNA polymerase, caused by a one-step mutation in the
rpoβ gene. The incidence of rifapentine resistant mutants in an otherwise
susceptible population of M. tuberculosis strains is approximately one
in 107 to 108 bacilli. Rifapentine resistance appears to
be associated with monotherapy. Therefore, rifapentine should always be used in
combination with other antituberculosis drugs.

Cross Resistance

M. tuberculosis organisms resistant to
other rifamycins are likely to be resistant to rifapentine. A high level of
cross-resistance between rifamycin and rifapentine has been demonstrated with M.
tuberculosis strains. Cross-resistance between rifapentine and
non-rifamycin antimycobacterial agents has not been identified in clinical
isolates.

Susceptibility Test Methods

In vitro susceptibility tests
should be performed according to published methods1. Susceptibility
test interpretive criteria and quality control ranges for in vitro
susceptibility testing of Rifapentine have not been established.

Clinical Studies

Active Pulmonary Tuberculosis

PRIFTIN was studied in two randomized, open-label
controlled clinical trials in the treatment of active pulmonary tuberculosis.

The first trial was an open-label, prospective, parallel
group, active controlled trial in HIV-negative patients with active pulmonary
tuberculosis. The population mostly comprised Black (approximately 60%) or
multiracial (approximately 31%) patients. Treatment groups were comparable for
age and sex and consisted primarily of male subjects with a mean age of 37 ± 11
years. In the initial 2 month phase of treatment, 361 patients received PRIFTIN
600 mg twice a week in combination with daily isoniazid, pyrazinamide, and
ethambutol and 361 subjects received rifampin600 mg in combination with
isoniazid, pyrazinamide and ethambutol all administered daily. The doses of the
companion drugs were the same in both treatment groups during the initial
phase: isoniazid 300 mg, pyrazinamide 2000 mg, and ethambutol 1200 mg. For
patients weighing less than 50 kg, the doses of rifampin (450 mg), pyrazinamide
(1500 mg) and ethambutol (800 mg) were reduced. Ethambutol was discontinued
when isoniazid and rifampin susceptibility testing results were confirmed.
During the 4 month continuation phase, 317 patients in the PRIFTIN group
continued to receive PRIFTIN 600 mg dosed once-weekly with isoniazid 300 mg and
304 patients in the rifampin group received twice weekly rifampin and isoniazid
900 mg. For patients weighing less than 50 kg, the doses of rifampin (450 mg)
and isoniazid (600 mg) were reduced. Both treatment groups received pyridoxine
(Vitamin B6) over the 6 month treatment period. Treatment was directly
observed. 65/361 (18%) of patients in the PRIFTIN group and 34/361 (9%) in the
rifampin group received overdoses of one or more of the administered study
medications during the initial or continuation phase of treatment. Seven of
these patients had adverse reactions reported with the overdose (5 in the
PRIFTIN group and 2 in the rifampin group).

Table 8 below contains assessments of sputum conversion
at end of treatment (6 months) and relapse rates at the end of follow-up (24
months).

Risk of relapse was greater in
the group treated with the PRIFTIN combination. Higher relapse rates were
associated with a lower rate of compliance as well as a failure to convert
sputum cultures at the end of the initial 2 month treatment phase. Relapse
rates were also higher for males in both regimens. Relapse in the PRIFTIN group
was not associated with development of mono-resistance to rifampin.

The second trial was
randomized, open-label performed in 1075 HIV-negative and positive patients
with active pulmonary tuberculosis. Patients with culture-positive,
drug-susceptible pulmonary tuberculosis who had completed the initial 2-month
phase of treatment with 4 drugs (rifampin, isoniazid, pyrazinamide, and either
ethambutol or streptomycin) under direct observation were randomly assigned to
receive either PRIFTIN 600 mg and isoniazid 15 mg/kg (max 900 mg) once-weekly
or rifampin 10 mg/kg (max 600 mg) and isoniazid 15 mg/kg (max 900 mg) twice
weekly for the 4 month continuation phase. Study drugs were given under direct
observation therapy in both groups.

In the PRIFTIN group, 502
HIV-negative and 36 HIV-positive patients were randomized and in the rifampin
group 502 HIV-negative and 35 HIV-positive patients were randomized to
treatment. Enrollment of HIV-infected patients was stopped when 4 of 36 patients
in the PRIFTIN combination group relapsed with isolates that were rifampin
resistant.

Table 9 below contains
assessments of sputum conversion at the end of treatment (6 months total: 2
months of initial and 4 months of randomized continuation treatment) and
relapse rates at the end of follow-up (24 months) in all HIV-negative patients
randomized to treatment. Positive culture was based on either one sputum sample
with > 10 colonies on solid media OR at least 2 positive sputum samples on
liquid or solid media. However, only one sputum sample was collected at each
visit in a majority of patients.

* Treatment response was defined as subjects who had two
negative sputum cultures after 16 doses of rifampin and isoniazid or after 8
doses of PRIFTIN and isoniazid, and remained sputum negative through the end of
continuation phase therapy.
** Due to drug toxic effects, non-adherence,
withdrawal of consent, receipt of non-study regimen, other.

In HIV-negative patients,
higher relapse rates were seen in patients with a positive sputum culture at 2
months (i.e., at the time of study randomization), cavitation on chest x-ray,
and bilateral pulmonary involvement.

Sixty-one HIV-positive patients
were assessed for relapse. The rates of relapse were 16.7% (5/30) in the
PRIFTIN group and 9.7% (3/31) in the rifampin group. In HIV-positive patients,
4 of the 5 relapses in the PRIFTIN combination group involved M. tuberculosis strains
with rifampin monoresistance. No relapse strain in the twice weekly rifampin /
isoniazid group acquired drug resistance.

The death rate among all study
participants did not differ between the two treatment groups.

Latent Tuberculosis Infection

A multi-center, prospective,
open-label, randomized, active-controlled trial compared the effectiveness of
12 weekly doses of PRIFTIN in combination with isoniazid (3RPT/INH arm)
administered by directly observed therapy to 9 months of self-administered
daily isoniazid (9INH arm). The trial enrolled patients two years of age or
older with positive tuberculin skin test and at high risk for progression to
tuberculosis disease. Enrolled patients included those having close contact
with a patient with active tuberculosis disease, recent (within two years)
conversion to a positive tuberculin skin test, HIV-infection, or fibrosis on
chest radiograph. PRIFTIN was dosed by weight, for a maximum of 900 mg weekly.
Isoniazid mg/kg dose was determined by age, for a maximum of 900 mg weekly in
the 3RPT/INH arm and 300 mg daily in the 9INH arm [see DOSING AND
ADMINISTRATION].

The outcome measure was the development of active
tuberculosis disease, defined as culture confirmed tuberculosis in adults and
culture-confirmed or clinical tuberculosis in children less than 18 years of
age, at 33 months after trial enrollment. Patients who were found after
enrollment to be ineligible because they had active tuberculosis disease, were
contacts of a source case with culture-negative or drug-resistant tuberculosis
disease cases or no information regarding susceptibility of M. tuberculosis,
and young children lacking a positive TST on initial and repeat testing were
excluded from the analysis.

Active tuberculosis disease developed in 5 of 3074
randomized patients in the 3RPT/INH group (0.16%) versus 10 of 3074 patients in
9INH group (0.32%), for a difference in cumulative rates of 0.17%, 95% CI
(-0.43, 0.09) (Table 10).

* Similar results were observed
when all enrolled patients were included in the analysis.
** Rate in the 3RPT/INH group minus the rate in the 9INH group.

The proportion of patients
completing treatment was 81.2% in the 3RPT/INH group and 68.3% in the 9INH
group for a difference (3RPT/INH-9INH) of 12.8% 95% CI (10.7, 15.0).

In the 9INH treatment group,
two of the thirteen culture-confirmed cases were found to be isoniazid
-monoresistant. In the 3RPT/INH treatment group, one of the seven cases was
rifampin -resistant, isoniazid -susceptible M. bovis infection.

Pediatric Sub-study

Enrollment of children was
extended after the overall target number of patients was attained in the main
study. Data from both the main study and the extension were pooled resulting in
an eligible population for analysis of 375 children in the 3RPT/INH arm and 367
in the 9INH arm.

One child in the 9INH group
developed tuberculosis (1/367, cumulative rate 0.32%) versus zero tuberculosis
cases in the 3RPT/INH group (0/375) at 33 months post-enrollment. The
proportion of patients completing treatment in the 3RPT/INH and the 9INH groups
was 87.5% and 79.6% respectively for a difference of 7.9%, 95% CI (2.5, 13.2).

HIV Sub-study

Enrollment of HIV-positive
patients was extended after the overall target number of patients was attained
in the main study. Data from both the main study and the extension were pooled
resulting in an eligible population for analysis of 206 patients in the
3RPT/INH group and 193 in the 9INH group. Tuberculosis disease developed
in 2/206 patients in the 3RPT/INH group (cumulative rate, 1.01%) and in 6/193
patients in the 9INH group (cumulative rate, 3.45%). The proportion of patients
completing treatment in the 3RPT/INH and 9INH groups was 88.8% and 63.7%,
respectively for a difference of 25.1%, 95% CI (16.8, 32.9).